The prevalence of obesity has grown at alarming rates, reaching pandemic proportions. One third of U.S. adults are obese, leading to increased numbers of patients affected by the comorbidities of obesity, such as cardiovascular disease, type 2 diabetes, respiratory disorders and cancer (Wang et al., 2011). Considering the staggering cost and serious challenges to public health associated with this condition, identification of biochemical pathways that can be effectively and safely targeted for obesity therapy has acquired new urgency.
Hypothalamic neurons expressing agouti-related protein (AgRP) have been directly implicated in promoting feeding. AgRP neuron activation by either light-gated Channelrhodopsin-2 or ligand-activated G-proteins rapidly increases food intake (Aponte et al., 2011; Krashes et al., 2011). Conversely, acute ablation of AgRP neurons in adulthood causes cessation of feeding and results in starvation (Luquet et al., 2005). Despite the established functional importance of AgRP neurons in feeding behavior, genetic analyses of specific hormonal pathways that impinge on this process have yielded limited and occasionally conflicting results. For example, transgenic overexpression of AgRP results in obesity, and acute intracerebroventricular delivery of AgRP or Neuropeptide Y (Npy), another peptide produced in AgRP neurons, elicits hyperphagia (Levine et al., 2004; Ollmann et al., 1997; Rossi et al., 1998). However, mice with loss of AgRP, Npy, or both exhibit no feeding or body weight phenotypes and maintain a normal response to starvation (Qian et al., 2002).
The key anorexigenic hormones, insulin and leptin, inhibit AgRP neurons, raising their activation threshold (Konner et al., 2007; Takahashi and Cone, 2005). Surprisingly though, genetic ablation of insulin receptor in AgRP neurons has no effect on energy homeostasis, even though it impairs insulin-mediated suppression of hepatic glucose production (Konner et al., 2007). Similarly, inactivation of leptin receptors in AgRP neurons results in a mild increase of weight, without affecting feeding behavior and energy balance (van de Wall et al., 2008). Thus, neither pathway appears to exert obligate control over AgRP neuron-dependent feeding and energy homeostasis. There is a need to solve the apparent paradox of the absence of food intake abnormalities following ablation of leptin or insulin receptors, and to identify alternative pathways that regulate AgRP neuron-dependent food intake.